Amines as pharmaceutical agents

ABSTRACT

Novel gamma aminobutyric acids of formula (I) are disclosed and are useful as agents in the treatment of epilepsy, faintness attacks, hypokinesia, cranial disorders, neurodegenerative disorders, depression, anxiety, panic, pain, neuropathological disorders, inflammation, and gastrointestinal damage. Processes for the preparation and intermediates useful in the preparation are also disclosed.

This application claims benefit of Provisional Applications No.60/069,773 filed Dec. 16, 1997 and No. 60/104,924 filed Oct. 20, 1998.

BACKGROUND OF THE INVENTION

Compounds of formula

wherein R₁ is hydrogen or a lower alkyl radical and n is 4, 5, or 6 areknown in U.S. Pat. No. 4,024,175 and its divisional U.S. Pat. No.4,087,544. The uses disclosed are: protective effect against crampinduced by thiosemicarbazide; protective action against cardiazolecramp; the cerebral diseases, epilepsy, faintness attacks, hypokinesia,and cranial traumas; and improvement in cerebral functions. Thecompounds are useful in geriatric patients. The patents are herebyincorporated by reference.

Compounds of formula

wherein R₁ is a straight or branched alkyl group having from 1 to 6carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms; R₂is hydrogen or methyl; and R₃ is hydrogen, methyl, or carboxyl are knownin U.S. Pat. No. 5,563,175 and various divisionals. These patents arehereby incorporated by reference.

SUMMARY OF THE INVENTION

The compounds of the instant invention are novel amines and theirpharmaceutically acceptable salts useful in a variety of disorders. Thedisorders include: epilepsy, faintness attacks, hypokinesia, cranialdisorders, neurodegenerative disorders, depression, anxiety, panic,pain, neuropathological disorders, inflammation, and gastrointestinaldisorders.

The compounds of the invention are those of formulas 1A and 1B below.

Preferred compounds are those of formulas 1A and 1B wherein R is asulfonamide selected from —NHSO₂R¹⁵ or —SO₂NHR¹⁵ wherein R¹⁵ is straightor branched alkyl or trifluoromethyl.

Especially preferred are:

4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine;

3-(2-Aminomethyl-4-methyl-pentyl )-4H-[1,2,4]oxadiazole-5-thione, HCl;

3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one, HCl;

(2-Aminomethyl-4-methyl-pentyl)-phosphonic acid;

3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]oxadiazol-5-one;

3-(3-Amino-2-cyclopentyl-propyl)-4H-[1,2,4]thiadiazol-5-one;

2-Cyclopentyl-3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-propylamine;

3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]oxadiazol-5-one;

3-(3-Amino-2-cyclobutyl-propyl)-4H-[1,2,4]thiadiazol-5-one; and

2-Cyclobutyl-3-(2-oxo-2,3-dihydro-2λ⁴-[1,2,3,5]oxathiadiazol-4-yl)-propylamine.

Other preferred compounds are those of formulas 1A and 1B wherein R is aphosphonic acid, —PO₃H₂.

Other preferred compounds are those of Formulas 1A and 1B wherein

Especially preferred are:

DETAILED DESCRIPTION OF THE INVENTION

The amines of the instant invention are compounds of formula 1A and 1Band the pharmaceutically acceptable salts thereof.

The compounds of the invention are those of formula

or a pharmaceutically acceptable salt thereof wherein:

n is an integer of from 0 to 2;

R is sulfonamide,

amide,

phosphonic acid,

heterocycle,

sulfonic acid, or

hydroxamic acid;

A is hydrogen or methyl; and

 straight or branched alkyl of from 1 to 11 carbons, or—(CH₂)₁₋₄—Y—(CH₂)₀₋₄-phenyl wherein Y is —O—, —S—, —NR′₃ wherein R′₃ isalkyl of from 1 to 6 carbons, cycloalkyl of from 3 to 8 carbons, benzylor phenyl wherein benzyl or phenyl can be unsubstituted or substitutedwith from 1 to 3 substituents each independently selected from alkyl,alkoxy, halogen, hydroxy, carboxy, carboalkoxy, trifluoromethyl, andnitro.

Since amino acids are amphoteric, pharmacologically compatible salts canbe salts of appropriate inorganic or organic acids, for example,hydrochloric, sulphuric, phosphoric, acetic, oxalic, lactic, citric,malic, salicylic, malonic, maleic, succinic, methanesulfonic acid, andascorbic. Starting from corresponding hydroxides or carbonates, saltswith alkali metals or alkaline earth metals, for example, sodium,potassium, magnesium, or calcium are formed. Salts with quaternaryammonium ions can also be prepared with, for example, thetetramethyl-ammonium ion. The carboxyl group of the amino acids can beesterified by known means.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

The terms used to define the invention are as described below.

Sulfonamides are those of formula —NHSO₂R¹⁵ or —SO₂NHR¹⁵ wherein R¹⁵ isa straight or branched alkyl group of from 1 to 6 carbons or atrifluoromethyl.

Amides are compounds of formula —NHCOR¹² wherein R¹² is straight orbranched alkyl of from 1 to 6 carbons, benzyl, and phenyl.

Phosphonic acids are —PO₃H₂.

Sulfonic acids are —SO₃H.

Hydroxamic acid is

Heterocycles are groups of from 1 to 2 rings, with from 1 to 6heteroatoms selected from oxygen, nitrogen, and sulfur.

Preferred heterocycles are

The term alkyl is a straight or branched group of from 1 to 11 carbonatoms including but not limited to methyl, ethyl, propyl, n-propyl,isopropyl, butyl, 2-butyl, tert-butyl, pentyl, hexyl, and n-hexyl,heptyl, octyl, nonyl, decyl, and undecyl except as where otherwisestated.

The cycloalkyl groups are from 3 to 8 carbons and are cyclopropyl,cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl unlessotherwise stated.

The benzyl and phenyl groups may be unsubstituted or substituted by from1 to 3 substituents selected from hydroxy, carboxy, carboalkoxy,halogen, CF₃, nitro, alkyl, and alkoxy. Preferred are halogens.

Alkoxy is as defined above for alkyl.

Halogen is fluorine, chlorine, and bromine and preferred are fluorineand chlorine.

Carboalkoxy is —COOalkyl wherein alkyl is as described above. Preferredare carbomethoxy and carboethoxy.

Certain of the compounds of the present invention can exist inunsolvated forms as well as solvated forms, including hydrated forms. Ingeneral, the solvated forms, including hydrated forms, are equivalent tounsolvated forms and are intended to be encompassed within the scope ofthe present invention.

Certain of the compounds of the present invention possess one or morechiral centers and each center may exist in the R(D) or S(L)configuration. The present invention includes all enantiomeric andepimeric forms as well as the appropriate mixtures thereof.

The radioligand binding assay using [³H]gabapentin and the α₂δ subunitderived from porcine brain tissue was used (“The Novel Anti-convulsantDrug, Gabapentin, Binds to the a α₂δ Subunit of a Calcium Channel”, GeeN. S., et al., J. Biol Chem, 1996;271(10):5768-5776).

The compounds of the invention show good binding affinity to the α₂δsubunit. Gabapentin (Neurontin®) is about 0.10 to 0.12 μM in this assay.Since the compounds of the instant invention also bind to the subunit,they are expected to exhibit pharmacologic properties comparable togabapentin. For example, as agents for convulsions, anxiety, and pain.

TABLE 1

Vogel α2δ Pain Model Conflict DBA2 Assay % MPE % of % Protection R IC₅₀(μM) 1 Hr 2 Hr CI-1008 1 Hr 2 Hr

2.47 0 0 0.0 0 0

>10 0 0

1.52 PO₃H₂ >10 0 0

The compounds of the invention are related to Neurontin®, a marketeddrug effective in the treatment of epilepsy. Neurontin® is1-(aminomethyl)-cyclohexaneacetic acid of structural formula

Preferred novel gabapentin and isobutyl-GABA analogs, their derivatives,and pharmaceutically acceptable salts are useful in the treatment of avariety of disorders including epilepsy, faintness attacks, hypokinesia,cranial disorders, neurodegenerative disorders, depression, anxiety,panic, pain, and neuropathological disorders. The compounds are of thegeneral formula:

a pharmaceutically acceptable salt thereof or a prodrug thereof, wheren=0,1,2, m=0,1,2,3, and R can be sulfonamides of the general formula—NHSO₂R¹ or —SO₂NHR¹ where R¹ is H or C₁-C₄ straight or branched chainalkyl or trifluoromethyl. R may also be an amide of the general formula—NHCOR¹. Or R may also be a phosphonic acid —PO₃H₂ (Lipinski C. A., Ann.Rep. Med. Chem., 21:283 (1986)).

The compounds of the invention are also expected to be useful in thetreatment of epilepsy.

The present invention also relates to therapeutic use of the compoundsof the mimetic as agents for neurodegenerative disorders.

Such neurodegenerative disorders are, for example, Alzheimer's disease,Huntington's disease, Parkinson's disease, Amyotrophic LateralSclerosis, and epilepsy.

The present invention also covers treating neurodegenerative disorderstermed acute brain injury. These include but are not limited to: stroke,head trauma, and asphyxia.

Stroke refers to a cerebral vascular disease and may also be referred toas a cerebral vascular incident (CVA) and includes acute thromboembolicstroke. Stroke includes both focal and global ischemia. Also, includedare transient cerebral ischemic attacks and other cerebral vascularproblems accompanied by cerebral ischemia such as in a patientundergoing carotid endarterectomy specifically or other cerebrovascularor vascular surgical procedures in general, or diagnostic vascularprocedures including cerebral angiography and the like.

Pain refers to acute as well as chronic pain.

Acute pain is usually short-lived and is associated with hyperactivityof the sympathetic nervous system. Examples are postoperative pain andallodynia.

Chronic pain is usually defined as pain persisting from 3 to 6 monthsand includes somatogenic pains and psychogenic pains. Other pain isnociceptive.

Still other pain is caused by injury or infection of peripheral sensorynerves. It includes, but is not limited to pain from peripheral nervetrauma, herpes virus infection, diabetes mellitus, causalgia, plexusavulsion, neuroma, limb amputation, and vasculitis. Neuropathic pain isalso caused by nerve damage from chronic alcoholism, humanimmunodeficiency virus infection, hypothyroidism, uremia, or vitamindeficiencies. Neuropathic pain includes, but is not limited to paincaused by nerve injury such as, for example, the pain diabetics sufferfrom.

Psychogenic pain is that which occurs without an organic origin such aslow back pain, atypical facial pain, and chronic headache.

Other types of pain are: inflammatory pain, osteoarthritic pain,trigeminal neuralgia, cancer pain, diabetic neuropathy, restless legsyndrome, acute herpetic and postherpetic neuralgia, causalgia, brachialplexus avulsion, occipital neuralgia, gout, phantom limb, burn, andother forms of neuralgia, neuropathic and idiopathic pain syndrome.

Other incidents are head trauma, spinal cord trauma, or injury fromgeneral anoxia, hypoxia, hypoglycemia, and hypotension as well assimilar injuries seen during procedures from embole, hyperfusion, andhypoxia.

The instant invention would be useful in a range of incidents, forexample, during cardiac bypass surgery, in incidents of intracranialhemorrhage, in perinatal asphyxia, in cardiac arrest, and statusepilepticus.

A skilled physician will be able to determine the appropriate situationin which subjects are susceptible to or at risk of, for example, strokeas well as suffering from stroke for administration by methods of thepresent invention.

The compounds of the invention are also expected to be useful in thetreatment of depression. Depression can be the result of organicdisease, secondary to stress associated with personal loss, oridiopathic in origin. There is a strong tendency for familial occurrenceof some forms of depression suggesting a mechanistic cause for at leastsome forms of depression. The diagnosis of depression is made primarilyby quantification of alterations in patients' mood. These evaluations ofmood are generally performed by a physician or quantified by aneuropsychologist using validated rating scales, such as the HamiltonDepression Rating Scale or the Brief Psychiatric Rating Scale. Numerousother scales have been developed to quantify and measure the degree ofmood alterations in patients with depression, such as insomnia,difficulty with concentration, lack of energy, feelings ofworthlessness, and guilt. The standards for diagnosis of depression aswell as all psychiatric diagnoses are collected in the Diagnostic andStatistical Manual of Mental Disorders (Fourth Edition) referred to asthe DSM-IV-R manual published by the American Psychiatric Association,1994.

GABA is an inhibitory neurotransmitter with the central nervous system.Within the general context of inhibition, it seems likely thatGABA-mimetics might decrease or inhibit cerebral function and mighttherefore slow function and decrease mood leading to depression.

The compounds of the instant invention may produce an anticonvulsanteffect through the increase of newly created GABA at the synapticjunction. If gabapentin does indeed increase GABA levels or theeffectiveness of GABA at the synaptic junction, then it could beclassified as a GABA-mimetic and might decrease or inhibit cerebralfunction and might, therefore, slow function and decrease mood leadingto depression.

The compounds of the invention will be useful in the treatment ofgastrointestinal disorders, especially irritable bowel syndrome.

The fact that a GABA agonist or GABA-mimetic might work just theopposite way by increasing mood and thus, be an antidepressant, is a newconcept, different from the prevailing opinion of GABA activityheretofore.

The compounds of the instant invention are also expected to be useful inthe treatment of anxiety and of panic as demonstrated by means ofstandard pharmacological procedures.

MATERIAL AND METHODS

Carrageenin-Induced Hyperalgesia

Nociceptive pressure thresholds were measured in the rat paw pressuretest using an analgesymeter (Randall-Sellitto Method: Randall L. O.,Sellitto J. J., A method for measurement of analgesic activity oninflamed tissue. Arch. Int. Pharmacodyn., 4:409-419 (1957)). MaleSprague-Dawley rats (70-90 g) were trained on this apparatus before thetest day. Pressure was gradually applied to the hind paw of each rat andnociceptive thresholds were determined as the pressure (g) required toelicit paw withdrawal. A cutoff point of 250 g was used to prevent anytissue damage to the paw. On the test day, two to three baselinemeasurements were taken before animals were administered 100 μL of 2%carrageenin by intraplantar injection into the right hind paw.Nociceptive thresholds were taken again 3 hours after carrageenin toestablish that animals were exhibiting hyperalgesia. Animals were dosedwith either gabapentin (3-300 mg/kg, s.c.), morphine (3 mg/kg, s.c.), orsaline at 3.5 hours after carrageenin and nociceptive thresholds wereexamined at 4, 4.5, and 5 hours post carrageenin.

Semicarbazide-Induced Tonic Seizures

Tonic seizures in mice are induced by subcutaneous administration ofsemicarbazide (750 mg/kg). The latency to the tonic extension offorepaws is noted. Any mice not convulsing within 2.0 hours aftersemicarbazide are considered protected and given a maximum latency scoreof 120 minutes.

Animals

Male Hooded Lister rats (200-250 g) are obtained from Interfauna(Huntingdon, UK) and male TO mice (20-25 g) are obtained from Bantin andKingman (Hull, UK). Both rodent species are housed in groups of six. TenCommon Marmosets (Callithrix Jacchus) weighing between 280 and 360 g,bred at Manchester University Medical School (Manchester, UK) are housedin pairs. All animals are housed under a 12-hour light/dark cycle(lights on at 07.00 hour) and with food and water ad libitum.

Drug Administration

Drugs are administered either intraperitoneally (IP) or subcutaneously(SC) 40 minutes before the test in a volume of 1 mL/kg for rats andmarmosets and 10 mL/kg for mice.

Mouse Light/Dark Box

The apparatus is an open-topped box, 45 cm long, 27 cm wide, and 27 cmhigh, divided into a small (2/5) and a large (3/5) area by a partitionthat extended 20 cm above the walls (Costall B., et al., Exploration ofmice in a black and white box: validation as a model of anxiety.Pharmacol. Biochem. Behav., 32:777-785 (1989)).

There is a 7.5×7.5 cm opening in the center of the partition at floorlevel. The small compartment is painted black and the large compartmentwhite. The white compartment is illuminated by a 60-W tungsten bulb. Thelaboratory is illuminated by red light. Each mouse is tested by placingit in the center of the white area and allowing it to explore the novelenvironment for 5 minutes. The time spent in the illuminated side ismeasured (Kilfoil T., et al., Effects of anxiolytic and anxiogenic drugson exploratory activity in a simple model of anxiety in mice.Neuropharmacol., 28:901-905 (1989)).

Rat Elevated X-Maze

A standard elevated X-maze (Handley S. L., et al., Effects ofalpha-adrenoceptor agonists and antagonists in a maze-exploration modelof ‘fear’-motivated behavior. Naunyn-Schiedeberg's Arch. Pharmacol.,327:1-5 (1984)), was automated as previously described (Field, et al.,Automation of the rat elevated X-maze test of anxiety. Br. J.Pharmacol., 102(Suppl):304P (1991)). The animals are placed on thecenter of the X-maze facing one of the open arms. For determininganxiolytic effects the entries and time spent on the end half sectionsof the open arms is measured during the 5-minute test period (Costall,et al., Use of the elevated plus maze to assess anxiolytic potential inthe rat. Br. J. Pharmacol., 96(Suppl):312P (1989)).

Marmoset Human Threat Test

The total number of body postures exhibited by the animal towards thethreat stimulus (a human standing approximately 0.5 m away from themarmoset cage and staring into the eyes of the marmoset) is recordedduring the 2-minute test period. The body postures scored are slitstares, tail postures, scent marking of the cage/perches, piloerection,retreats, and arching of the back. Each animal is exposed to the threatstimulus twice on the test day before and after drug treatment. Thedifference between the two scores is analyzed using one-way analysis ofvariance followed by Dunnett's t-test. All drug treatments are carriedout SC at least 2 hours after the first (control) threat. Thepretreatment time for each compound is 40 minutes.

Rat Conflict Test

Rats are trained to press levers for food reward in operant chambers.The schedule consists of alternations of four 4-minute unpunishedperiods on variable interval of 30 seconds signaled by chamber lights onand three 3-minute punished periods on fixed ratio 5 (by footshockconcomitant to food delivery) signaled by chamber lights off. The degreeof footshock is adjusted for each rat to obtain approximately 80% to 90%suppression of responding in comparison with unpunished responding. Ratsreceive saline vehicle on training days.

The compounds of the instant invention are also expected to be useful inthe treatment of pain and phobic disorders (Am. J. Pain Manag., 5:7-9(1995)).

The compounds of the instant invention are also expected to be useful intreating the symptoms of manic, acute or chronic, single upside, orrecurring depression. They are also expected to be useful in treatingand/or preventing bipolar disorder (U.S. Pat. No. 5,510,381).

TNBS-Induced Chronic Visceral Allodynia In Rats

Injections of trinitrobenzene sulfonic (TNBS) into the colon have beenfound to induce chronic colitis. In human, digestive disorders are oftenassociated with visceral pain. In these pathologies, the visceral painthreshold is decreased indicating a visceral hypersensitivity.Consequently, this study was designed to evaluate the effect ofinjection of TNBS into the colon on visceral pain threshold in aexperimental model of colonic distension.

Animals and Surgery

Male Sprague-Dawley rats (Janvier, Le Genest-St-Ilse, France) weighing340-400 g are used. The animals are housed 3 per cage in a regulatedenvironment (20±1° C., 50±5% humidity, with light 8:00 am to 8:00 pm).Under anesthesia (ketamine 80 mg/kg ip; acepromazin 12 mg/kg ip), theinjection of TNBS (50 mg/kg) or saline (1.5 mL/kg) is performed into theproximal colon (1 cm from the cecum). After the surgery, animals areindividually housed in polypropylene cages and kept in a regulatedenvironment (20±1° C., 50±5% humidity, with light 8:00 am to 8:00 pm)during 7 days.

Experimental Procedure

At Day 7 after TNBS administration, a balloon (5-6 cm length) isinserted by anus and kept in position (tip of balloon 5 cm from theanus) by taping the catheter to the base of the tail. The balloon isprogressively inflated by step of 5 mm Hg, from 0 to 75 mm Hg, each stepof inflation lasting 30 seconds. Each cycle of colonic distension iscontrolled by a standard barostat (ABS, St-Dié, France). The thresholdcorresponds to the pressure which produced the first abdominalcontraction and the cycle of distension is then discontinued. Thecolonic threshold (pressure expressed in mm Hg) is determined afterperformance of four cycles of distension on the same animal.

Determination of the Activity of the Compound

Data is analyzed by comparing test compound-treated group withTNBS-treated group and control group. Mean and sem are calculated foreach group. The antiallodynic activity of the compound is calculated asfollows:

Activity (%)=(group C—group T)/(group A—group T)

Group C: mean of the colonic threshold in the control group

Group T: mean of the colonic threshold in the TNBS-treated group

Group A: mean of the colonic threshold in the test compound-treatedgroup

Statistical Analysis

Statistical significance between each group was determined by using aone-way ANOVA followed by Student's unpaired t-test. Differences wereconsidered statistically significant at p<0.05.

Compounds

TNBS is dissolved in EtOH 30% and injected under a volume of 0.5 mL/rat.TNBS is purchased from Fluka.

Oral administration of the test compound or its vehicle is performed 1hour before the colonic distension cycle.

Sub-cutaneous administration of the test compound or its vehicle isperformed 30 minutes before the colonic distension cycle.

The compounds of the present invention can be prepared and administeredin a wide variety of oral and parenteral dosage forms. Thus, thecompounds of the present invention can be administered by injection,that is, intravenously, intramuscularly, intracutaneously,subcutaneously, intraduodenally, or intraperitoneally. Also, thecompounds of the present invention can be administered by inhalation,for example, intranasally. Additionally, the compounds of the presentinvention can be administered transdermally. It will be obvious to thoseskilled in the art that the following dosage forms may comprise as theactive component, either a compound of Formula I or a correspondingpharmaceutically acceptable salt of a compound of Formula I.

For preparing pharmaceutical compositions from the compounds of thepresent invention, pharmaceutically acceptable carriers can be eithersolid or liquid. Solid form preparations include powders, tablets,pills, capsules, cachets, suppositories, and dispersible granules. Asolid carrier can be one or more substances which may also act asdiluents, flavoring agents, binders, preservatives, tabletdisintegrating agents, or an encapsulating material.

In powders, the carrier is a finely divided solid which is in a mixturewith the finely divided active component.

In tablets, the active component is mixed with the carrier having thenecessary binding properties in suitable proportions and compacted inthe shape and size desired.

The powders and tablets preferably contain from five or ten to aboutseventy percent of the active compound. Suitable carriers are magnesiumcarbonate, magnesium stearate, talc, sugar, lactose, pectin, dextrin,starch, gelatin, tragacanth, methylcellulose, sodiumcarboxymethylcellulose, a low melting wax, cocoa butter, and the like.The term “preparation” is intended to include the formulation of theactive compound with encapsulating material as a carrier providing acapsule in which the active component with or without other carriers, issurrounded by a carrier, which is thus in association with it.Similarly, cachets and lozenges are included. Tablets, powders,capsules, pills, cachets, and lozenges can be used as solid dosage formssuitable for oral administration.

For preparing suppositories, a low melting wax, such as a mixture offatty acid glycerides or cocoa butter, is first melted and the activecomponent is dispersed homogeneously therein, as by stirring. The moltenhomogenous mixture is then poured into convenient sized molds, allowedto cool, and thereby to solidify.

Liquid form preparations include solutions, suspensions, and emulsions,for example, water or water propylene glycol solutions. For parenteralinjection liquid preparations can be formulated in solution in aqueouspolyethylene glycol solution.

Aqueous solutions suitable for oral use can be prepared by dissolvingthe active component in water and adding suitable colorants, flavors,stabilizing and thickening agents as desired.

Aqueous suspensions suitable for oral use can be made by dispersing thefinely divided active component in water with viscous material, such asnatural or synthetic gums, resins, methylcellulose, sodiumcarboxymethylcellulose, and other well-known suspending agents.

Also included are solid form preparations which are intended to beconverted, shortly before use, to liquid form preparations for oraladministration. Such liquid forms include solutions, suspensions, andemulsions. These preparations may contain, in addition to the activecomponent, colorants, flavors, stabilizers, buffers, artificial andnatural sweeteners, dispersants, thickeners, solubilizing agents, andthe like.

The pharmaceutical preparation is preferably in unit dosage form. Insuch form the preparation is subdivided into unit doses containingappropriate quantities of the active component. The unit dosage form canbe a packaged preparation, the package containing discrete quantities ofpreparation, such as packeted tablets, capsules, and powders in vials orampoules. Also, the unit dosage form can be a capsule, tablet, cachet,or lozenge itself, or it can be the appropriate number of any of thesein packaged form.

The quantity of active component in a unit dose preparation may bevaried or adjusted from 0.1 mg to 1 g according to the particularapplication and the potency of the active component. In medical use thedrug may be administered three times daily as, for example, capsules of100 or 300 mg. The composition can, if desired, also contain othercompatible therapeutic agents.

In therapeutic use, the compounds utilized in the pharmaceutical methodof this invention are administered at the initial dosage of about 0.01mg to about 100 mg/kg daily. A daily dose range of about 0.01 mg toabout 100 mg/kg is preferred. The dosages, however, may be varieddepending upon the requirements of the patient, the severity of thecondition being treated, and the compound being employed. Determinationof the proper dosage for a particular situation is within the skill ofthe art. Generally, treatment is initiated with smaller dosages whichare less than the optimum dose of the compound. Thereafter, the dosageis increased by small increments until the optimum effect under thecircumstances is reached. For convenience, the total daily dosage may bedivided and administered in portions during the day, if desired.

R may also be a heterocycle such as tetrazole

or other heterocycles which have been used as replacements for CO₂H,such as

(Kohara Y., Kubo K., Imamiya E., Wada T., Inada Y., and Naka T., J. Med.Chem., 39:5228 (1996)).

Sulfonic and hydroxamic acids are also preferred. Tetrazoles of Formula1A can be synthesized by the route outlined in Scheme 1

The following examples are illustrative of the instant invention; theyare not intended to limit the scope.

EXAMPLE 1 4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine Compound 3 inScheme 1 {2-[(2-Cyano-ethylcarbamoyl)-methyl]-4-methyl-pentyl}-carbamicacid tert-butyl ester

A solution of compound 2 (8.0 g, 0.03 mol) (prepared in the usual mannerfrom (BOC)₂ and pregabalin) was taken up in 250 mL dry THF and cooled inan ice water bath. Triethyl amine (4.62 mL, 0.033 mol) was addedfollowed by the addition of isobutyle chloroformate (4 mL, 0.031 mol).The reaction was stirred at 0° C. for about 15 minutes during which timea precipitate formed. In a separate flask was placed3-aminoproprionitrile fumarate (3.95 g, 0.03 mol) in 35 mL of 1 M NaOHand 300 mL of THF. This mixture was cooled to 0° C. and treated with themixed anhydride formed above in four portions. Before each portion wasadded, 35 mL of 1 M NaOH was added to the mixture. The reaction wasstirred for 24 hours and was then concentrated to remove THF. Theresulting aqueous was extracted with three times ethyl acetate. Thecombined organic extracts were washed with brine, dried over magnesiumsulfate. The solvents were removed under reduced pressure to give 6.6 ggreen oil. MS(APCI) m/z 312 (M+1).

Compound 4 in Scheme 1[4-Methyl-2-(1-(2-cyano-ethyl)-tetrazol-5-ylmethyl)-pentyl]-carbamicacid tert-butyl ester and compound 5[4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentyl]-carbamic acid tert-butylester

The cyanoamide (6.5 g, 0.0209 mol) and triphenylphosphine (11.06 g,0.042 mol) were dissolved in 300 mL of dry THF. The solution was treatedwith DEAD (6.7 mL, 0.0425 mol) and TMSN₃ (5.75 mL, 0.043 mol). Thereaction was stirred for 24 hours, and the reaction mixture was cooledto 0° C. and treated with 900 mL of an aqueous solution containing 46.9g of (NH₄)₂Ce(IV)NO₃. The reaction mixture was concentrated to removeTHF and extracted with three portions of CH₂Cl₂. The combined organiclayers were dried with brine and Na₂SO₄ and the solvents were removedunder reduced pressure to give a clear oil which was passed through aplug of silicagel to give the product admixed with triphenylphospineoxide. This crude mixture was dissolved in 200 mL THF and 50 mL of 2NNaOH. The mixture was heated to reflux for 2 hours then stirred at roomtemperature overnight. The THF was removed under reduced pressure andthe resulting residue diluted with water. After extraction with ether,the aqueous phase was acidified to pH 7 and extracted with 21 mL of 4NHCl. The aqueous phase was then saturated with solid KH₂PO₄. The aqueousmixture was extracted with CH₂Cl₂. The organic extracts were washed withbrine and dried over Na₂SO₄. Evaporation of the organic solvents underreduced pressure resulted in isolation of 3.4 g of an amber oil.

4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine

The material from the previous step (0.9 g, 3.18 mmol) was taken up in20 mL of 4 M HCl in dioxane. The reaction was allowed to stand for 1hour. A solid formed, 10 mL of ether was added, and the reaction wasfiltered to give 780 mg white solid. MS(APCI) m/z 184 (M+1).

EXAMPLE 2 IsobutylGABA oxadiazolonethione (G) is also named3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-thione; HCl

BOC-IsobutylGABA (B)

A solution of di-tert-butyl dicarbonate (13.1 g, 0.06 mol) in THF (200mL) was added, over a 10-minute period, to a solution of isobutylGABA(9.95 g, 0.056 mol) in 1N NaOH (125 mL) and THF (50 mL) cooled in anice-water bath. The reaction mixture was stirred at room temperature 3hours, concentrated to remove THF, saturated with saturated KH₂PO₄ andextracted 3×EtOAc. The extracts were washed 2×brine, dried over MgSO₄,and evaporated to yield 13.8 g (95%) of a white solid, mp 84-88° C. MS(APCI) m/z 260 (M+1).

BOC-IsobutylGABA amide (C)

A solution of BOC-IsobutylGABA (6.78 g, 0.026 mol) and triethyl amine(3.0 g, 0.030 mol) was cooled to 0° C. and isobutyl chloroformate (3.9g, 0.029 mol) was slowly added. After stirring 20 minutes at 0° C.,ammonia gas was bubbled into the reaction mixture for 30 minutes, andthen the mixture was stirred at room temperature 18 hours. The mixturewas concentrated to remove THF, suspended in water, and extracted3×EtOAc. The extracts were washed 1×10% Na₂CO₃, 2×brine, and dried overNa₂SO₄. Evaporation yielded 4.9 g (73%) of an oil which was used withoutfurther purification. MS (APCI) m/z 259 (M+1).

BOC-IsobutylGABA nitrile (D)

A solution of BOC-IsobutylGABA amide (4.6 g, 0.0178 mol) in DMF (15 mL)was added, all at once, to cyanuric chloride (1.66 g, 0.009 mol) andstirred 30 minutes at room temperature. The reaction mixture was pouredinto a cold solution of NaHCO₃ (4.2 g, 0.05 mol) in water (150 mL).Solid K₂CO₃ was added to bring the pH to 9 and the mixture was extracted2×CH₂Cl₂, washed 1×brine, and dried over Na₂SO₄. Evaporation yielded anoil, which was filtered through silica gel, eluting with CH₂Cl₂-EtOAcwhich yielded 3.8 g oil (89%), which was used without furtherpurification. MS (APCI) m/z 240 (M), 239 (M−1); IR (Film) 2215 cm⁻¹.

BOC-IsobutylGABA amidoxime (E)

A solution of hydroxylamine was prepared by adding triethylamine (7.62g, 0.075 mol) to a suspension of hydroxylamine hydrochloride (5.21 g,0.075 mol) in DMSO (25 mL). After 15 minutes, the triethylaminehydrochloride was filtered off, and BOC-IsobutylGABA nitrile (3.61 g,0.015 mol) was added to the filtrate. The mixture was heated at 75° C.for 17 hours. The mixture was diluted with water and extracted 3×EtOAc.The extracts were washed 2×brine, dried over Na₂SO₄, and evaporated togive an oil which was filtered through a short silica gel column,eluting with CH₂Cl₂-EtOAc to give 3.2 g (78%) oil. ¹H NMR (CDCl₃) δ0.84(d, 6H, J=6.35 Hz), 1.11 (m, 2H), 1.40 (s, 9H), 1.63 (m, 1H), 3.05 (m,1H), 3.15 (m, 1H), 4.85 (m, 1H), 5.43 (m 1H); MS (APCI) 274 (M+1).

BOC-IsobutylGABA oxadiazolonethione (F)

A solution containing BOC-Isobutyl GABA amidoxime (0.5 g, 0.00183 mol),DBU (1.12 g, 0.00736 mol) and 90% 1,1′-thiocarbonyldiimidazole (0.398 g,0.002 mol) in MeCN (12 mL) was stirred at room temperature 16 hours. Thereaction mixture was evaporated to dryness, taken up in EtOAc, andwashed with KHSO₄ solution. The EtOAc layer was extracted with 1N NaOH(100 mL). The alkaline extract was washed with Et₂O and acidified withsaturated KH₂PO₄ and extracted 3×EtOAc. The extracts were washed1×water, 1×brine and dried over MgSO₄. Evaporation yielded an oil, 0.25g(43%). ¹H NMR (CDCl₃) δ0.84 (d, 6H, J=6.59 Hz), 1.1 (m, 2H), 1.41 (s,9H), 1.65 (m, 1H), 1.85 (m, 1H), 2.60 (m, 2H), 3.1 (m, 2H), 4.94 (m,1H), 12.8 (s, 1H). MS (APCI) 316 (M+1).

IsobutylGABA oxadiazolonethione (G) is also named3-(2-Aminomethyl-4-methyl-pentyl)4H-[1,2,4]oxadiazole-5-thione; HCl

BOC-IsobutylGABA oxadiazolonethione (0.25 g, 0.79 mmol) was taken up in4 M HCl in dioxane (10 mL) at room temperature for 1 hour. Evaporationfollowed by recrystallization of the residue from MeCN yieldedcream-colored crystals, 0.108 g, mp 183-185° C. ¹H NMR (DMSO-d₆) δ0.84(d, 6H, J=6.59 Hz), 1.1 (m, 2H), 1.41 (s, 9H), 1.65 (m, 1H), 0.80 (d,6H, J=6.59 Hz), 1.06 (m, 1H), 1.25 (m, 1H), 1.55 (m, 1H), 2.1 (m, 1H),2.7 (m, 4H), 7.95 (s, 3H); MS (APCI) 216 (M+1). Anal. Calcd forC₉H₁₇N₃OS.HCl: C, 42.93; H, 7.21; N, 16.69; Cl, 14.08. Found: C, 43.38;H, 7.24; N, 16.29; Cl, 14.17.

EXAMPLE 3 IsobutylGABA oxadiazolone (J) is also named3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one; HCl

BOC-IsobutylGABA amidoxime carbamate (H)

Isobutyl chloroformate (0.253 g, 0.00185 mol) was added dropwise to asolution of BOC-IsobutylGABA amidoxime (0.5 g, 0.00183 mol) and pyridine(0.158 g, 0.002 mol) in DMF (10 ml) at 0° C. After 30 minutes at thattemperature, the reaction mixture was diluted with water and extracted3×EtOAc. The extracts were washed 1×water, 1×brine and dried over MgSO₄.Evaporation yielded an oil, 0.7 g (100%) which was used without furtherpurification. MS (APCI) m/z 374 (M+1).

BOC-IsobutylGABA oxadiazolone (I)

BOC-IsobutylGABA amidoxime carbamate (0.7 g, 0.00183 mol) was taken upin xylene (20 mL) and heated under reflux 2 hours. Evaporation yielded adark glassy oil which was taken up in Et₂O and extracted with 1N NaOH.The alkaline phase was acidified with saturated KH₂PO₄ and extracted3×EtOAc. The extracts were washed with brine, dried over MgSO₄ andevaporated to yield a brown oil, 0.25 g (46%), which was used withoutfurther purification. MS (APCI) m/z 300 (M+1).

IsobutylGABA oxadiazolone (J) is also named3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one; HCl

BOC-IsobutylGABA oxadiazolone(0.25 g, 0.835 mmol) was taken up in 4 MHCl in dioxane and allowed to stand 2.5 hours Evaporation followed byrecrystallization of the residue from MeCN-Et₂O yielded a tan solid, 53mg (27%), mp 181-184° C. ¹H NMR (DMSO-d₆) δ0.80 (d, 6H, J=6.35 Hz), 1.1(m, 2H), 1.25 (s, 9H), 1.60 (m, 1H), 2.10 (m, 1H), 2.5-2.8 (m, 4H), 7.95(s, 3), 12.39 (s, 1H). MS (APCI) 216 (M+1). Anal. Calcd forC₉H₁₇N₃O₂.HCl: C, 45.86; H, 7.70; N, 17.83; Cl, 15.04. Found: C, 45.40;H, 7.55; N, 16.79; Cl, 15.81.

EXAMPLE 4 Preparation of (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid(9)

1. Preparation of 2-Isobutyl-succinic acid-4-t-butyl eser-1-methyl ester(2): 4-methylpentanoic acid methyl ester (10.0 g, 76.8 mmol) is added toa solution of LDA in 150 mL of THF at −78° C. under Ar. After 15minutes, the anion solution is added by cannula to a solution of t-butylbromoacetate (22.5 g, 115.2 mmol) in 50 mL of THF at −78° C., and thesolution is stirred for 45 minutes. The reaction mixture is then warmedto room temperature, and treated with 100 mL of saturated KH₂PO₄. TheTHF is evaporated, and the organics are extracted into Et₂O (3×50 mL).The Et₂O is washed with 10% Na₂S₂O₃ and dried with MgSO₄. The solvent isevaporated, and the remaining oil is distilled under vacuum (0.1 mm Hg)to give 11.1 g (59% yield) of 2-isobutyl-succinic acid4-t-butylester-1-methyl ester boiling at 65° C. to 72° C. NMR (H¹, 400 MHz,CDCl₃) δ0.9 (6H, m); δ1.2 (1H, m); δ1.4 (9H, s); δ1.5 (2H, m); δ2.3 (1H,dd); δ2.5 (1H, dd); δ2.8 (1H, m); δ3.6 (3H, s).

2. Preparation of 2-Isobutyl-succinic acid-4-t-butyl ester (3):2-isobutyl-succinic acid-4-t-butyl ester-1-methyl ester (11.1 g, 45.4mmol) and LiOH.H₂O (2.0 g, 47.7 mmol) are stirred in 180 mL of 3:1IPA/H₂O at room temperature overnight. The reaction mixture is extractedwith Et₂O (3×25 mL). The aqueous phase is acidified to pH=4, withsaturated KH₂PO₄ and extracted with Et₂O (3×50 mL). The Et₂O is driedover MgSO₄, and evaporated to give 8.0 g (77% yield) of2-isobutyl-succinic acid-4-t-butyl ester as an oil. NMR (H¹, 400 MHz,CDCl₃) δ0.9 (6H, m); δ1.3 (1H, m); δ1.4 (9H, s); δ1.6 (2H, m); δ2.3 (1H,dd); δ2.6 (1H, dd); δ2.8 (1H, m).

3. Preparation of 4-Isobutyl-dihydro-furan-2-one (4): A solution of2-isobutyl-succinic acid-4-t-butyl ester (8.0 g, 34.7 mmol) in 100 mL ofTHF is cooled to 0° C. under Ar and borane dimethyl sulphide complex(2.6 g, 34.7 mmol) is added. The reaction mixture is stirred at 0° C.for 10 minutes, and at room temperature overnight. The solution iscooled to 0° C. and 100 mL of MeOH is added. The solvents areevaporated, and the remaining oil is dried under hi-vacuum for 2 hrs.The oil remaining is taken up in 100 mL of THF, and a catalytic amountof p-toluene sulfonic acid is added. The solution is warmed to refluxovernight. After being cooled to room temperature, the solvent isevaporated, and the oil is taken up in Et₂O (100 mL). The Et₂O solutionis extracted with 2.0N Na₂CO₃ (2×50 mL) followed by 100 mL of brine anddried over MgSO₄. Evaporation of Et₂O followed by medium pressurechromatography (MPLC) of the remaining oil in 20% EtOAc/Hexanes gives4.4 g (89% yield) of 4-isopropyl-dihydro-furan-2-one as an oil. NMR (H¹,400 MHz, CDCl₃) δ0.9 (6H, m); δ1.3 (2H, dd); δ1.5 (1H, m); δ2.1 (1H, m);δ2.6 (2H, m); δ3.6 (1H, m); δ4.4 (1H, m).

4. Preparation of 3-Bromomethyl-3-isobutyl-propionic acid ethyl ester(5): A solution of 4-isopropyl-dihydro-furan-2-one (4.4 g, 30.9 mmol) inabsolute EtOH (50 mL) is cooled to 0° C. and saturated with HBr bypassing HBr gas through it for 10 minutes. The solution is warmed toroom temperature and stirred for 2.5 hours. It is diluted with 150 mL ofbrine and extracted with Et₂O (3×100 mL). Drying over MgSO₄ followed byevaporation of the solvent gives 4.9 g (63% yield) of3-bromomethyl-3-isobutyl-propionic acid ethyl ester as an oil. NMR (H¹,300 MHz, CDCl₃) δ0.9 (6H, d); δ1.3 (5, m); δ1.6 (1H, m); δ2.3(1H, m);δ2.5 (1H, dd); δ3.2 (1H, dd); δ3.6 (1H, dd); δ4.1 (2H, q).

5. Preparation of 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acidethyl ester (6): 3-bromomethyl-3-isobutyl-propionic acid ethyl ester(4.6 g, 18.3 mmol) is warmed in a 170° C. oil bath under Ar. Triethylphosphite (3.6 g, 22 mmol) is added dropwise over 2 hours. When additionis complete, the oil bath temperature is raised to 190° C. for 4 hours.The reaction mixture is cooled to room temperature, and the product ispurified by MPLC in EtOAc to give 2.7 g (48% yield) of3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester. NMR(H¹, 400 MHz, CDCl₃) δ0.8 (6H, d); δ1.2 (5H, m); δ1.3 (6H, m); δ1.6 (1H,m); δ1.7 (1H, d); δ1.8 (1H, d); 2.3 (2H, m); δ2.5 (1H, dd); δ4.1 (6H,m).

6. Preparation of 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid(7): 3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid ethyl ester(1.0 g, 3.2 mmol) and NaOH (1.8 mL, 2.0 M) are combined in 10 mL of EtOHat 0° C. After 15 minutes, the reaction mixture is warmed to roomtemperature and stirred overnight. The EtOH is evaporated, and 50 mL of2.0 M NaOH is added. The solution is extracted with Et₂O (2×50 mL), andthen acidified to pH=1 with concentrated HCl. The acidic solution isextracted with EtOAc (3×50 mL), and the combined extracts are dried overMgSO₄ and evaporated to give 0.65 g (72% yield) of3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid as an oil. NMR (H¹,400 MHz, CDCl₃) δ0.9 (6H, d); δ1.3 (8H, m); δ1.6 (1H, m); δ1.8 (2H, m);δ2.3 (1H, m); δ2.5 (2H, m); δ4.1 (4H, m).

7. Preparation of[2-(Benzyloxycarbonylamino-methyl)-4-methyl-pentyl]-phosphonic aciddiethyl ester (8): A solution3-(Diethoxy-phosphorylmethyl)-5-methyl-hexanoic acid (0.65 g, 2.3 mmol),diphenyl-di-phosphoryl-azide (0.76 g, 2.8 mmol), triethyl amine (0.47 g,4.6 mmol), and benzyl alcohol (0.5 g, 4.6 mmol) in 100 mL of toluene iswarmed to reflux overnight. The toluene is evaporated, and the remainingoil is taken up in 50 mL of EtOAc. The EtOAc solution is washed with1.0N HCl (2×50 mL), saturated NaHCO₃ (2×50 mL), and 50 mL of brine.Drying over Na₂SO₄ followed by evaporation of the solvent gives an oilwhich is purified by MPLC in EtOAc. Yield of[2-(Benzyloxycarbonylamino-methyl)-4-methyl-pentyl]-phosphonic aciddiethyl ester=0.46 g (52%). NMR (H¹, 400 MHz, CDCl₃) δ0.9 (6H, m);δ1.1-1.4 (9H, m); 1.7 (2H, m); δ2.0 (1H, m); δ3.1 (1H, m); δ3.3 (1H, m);δ4.1 (4H, q); δ5.0 (2H, s); δ5.7 (1H, bs); δ7.3 (5H, m).

8. Preparation of (2-Aminomethyl-4-methyl-pentyl)-phosphonic acid (9): Asolution of[2-(Benzyloxycarbonylamino-methyl)-4-methyl-pentyl]-phosphonic aciddiethyl ester (0.46 g, 1.2 mmol) in 20 mL of 47% aqueous HBr is warmedat reflux overnight. The solution is cooled to room temperature, and theH₂O is evaporated. The remaining solid is taken up in 10 mL of H₂O,filtered through Celite® 545, and passed through a Dowex® 50 ionexchange column (Bed Volume=30 mL). The column is eluted with 200 mL ofH₂O, 150 mL of 3% NH₄OH, and 150 mL of 10% NH₄OH. The basic eluates arecombined and evaporated to give 0.14 g of a white solid. After dryingunder vacuum at 60° C. with P₂O₂, the yield of(2-Aminomethyl-4-methyl-pentyl)-phosphonic acid=0.11 g (47%). NMR (H¹,400 MHz, CD₃OD) δ0.9 (6H, m); δ1.2 (2H, t); δ1.4 (1H, m); δ1.7 (2H, m);δ2.1 (1H, m); δ2.7 (1H, dd); δ3.0 (1H, dd). MS (m/e) 196 (M+1, 100%).Analysis for C₇H₁₈NO₃P: Calculated: C-43.07, H-9.29, N-7.18. Found:C-43.08, H-8.62, N-6.89.

What is claimed is:
 1. The compounds of the invention are those of theformula

or a pharmaceutically acceptable salt thereof wherein: n is an integerof from 0 to 2; and R is a heterocycle selected from


2. A compound according to claim 1 wherein n is 1 and R is


3. A compound according to claim 1 named:4-Methyl-2-(1H-tetrazol-5-ylmethyl)-pentylamine;3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-thione, HCL;and 3-(2-Aminomethyl-4-methyl-pentyl)-4H-[1,2,4]oxadiazole-5-one, HCl.4. A pharmaceutical composition comprising a therapeutically effectiveamount of a compound according to claim 1 and a pharmaceuticallyacceptable carrier.
 5. A method for treating pain comprisingadministering a therapeutically effective amount of a compound accordingto claim 1 to a mammal in need of said treatment.